There have hitherto been provided a number of substances having a therapeutic effect on skin and corneal diseases, in particular, wounds. For example, growth factors (BIO/Technology, 135-140, 1985) such as an epidermal growth factor (EGF) (Exp. Cell Res., 164, 1-10, 1986), acid and basic fibroblast growth factors (acid and basic FGFs). (J. Surg. Res., 45, 145-153, 1988), transforming growth factors (TGF-.alpha. and TGF-.beta.) (Japanese Patent Application Laid-Open No. 167231/1990; Science, 233, 532-534, 1986) and insulin-like growth factors (IGF-I and IGF-II), adhesion factors such as fibronectin, laminin and vitronectin (Ann. Rev. Biochem., 52, 961, 1983), and chemical substances such as retinoids and analogous compounds thereof (Am. J. Ophthalmol., 95, 353-358, 1983; Ann. Ophthal., 19, 175-180, 1987) have been known. The healing process of the skin wound is accompanied by granulation tissue formation, angiogenesis and re-epithelization. In these processes, fibroblasts, vascular endothelial cells and epidermal cells (keratinocytes) proliferate and migrate, respectively. The above-mentioned factors and other chemical substances have been known to be effective to the skin healing.
The healing process of the epithelia, parenchyma and endothelia of the cornea is accompanied by the migration and proliferation of epithelial cells, the phagocytosis of waste matter and the production of extracellular matrix by parenchymal cells, and the migration of endothelial cells, respectively.
In recent years, damages of endothelial cells have become recognized after cataract surgery, keratoplasty and wearing of contact lenses. Therefore, the importance of the endothelial cells has been pointed out. Human endothelial cells are said not to proliferate or to be hard to do. In their healing process, their migration and adhesion might be important. Up to the present, it has been reported that use of rabbit cultured endothelial cells which has proliferating ability revealed the fact that EGF and FGFs promote their proliferation. However, any effective remedy has not been yet reported. There is hence a demand for development of such an agent as promote the migration and adhesion of the endothelial cells.
On the other hand, as clinical pictures of skin diseases, in particular, psoriasis which is a chronic skin disease, there have been leukocyte infiltration (J. Invest. Dermatol., 68, 43-50, 1977), the hyperplasia of epidermis (J. Invest. Dermatol., 50, 254-258, 1968) and aberrant terminal differentiation (J. Invest. Dermatol., 70, 294-297, 1978), and as biochemical findings, there have been known, from the investigation on the mouse skins applied with a phorbol ester (TPA) which is a carcinogen, exhibiting psoriasis-like findings, the activation of protein kinase C (PKC) (J. Invest. Dermatol., 93, 379-386, 1989), increase in release of arachidonic acid and prostaglandin (Biochem. Biophys. Res. Commun., 92, 749-756, 1980), induction of ornithine dehydrogenase and transglutaminase activity (Cancer Res., 39, 4183-4188, 1979; Biochem. Biophys. Res. Commun., 97, 700-708, 1980) and increase in interleukin 1 (J. Invest. Dermatol., 88, 499A, 1987).
Steroid ointments and PUVA therapy have been used in local treatment for psoriasis, and dietetic therapy, vitamin D.sub.2, vitamin B.sub.12, etretinoids, etc. in general treatment. In recent years, TGF-.beta. having an antiproliferative effect on keratinocytes (Japanese Patent Application Laid-Open No. 167231/1990) and cyclosporin A having an antiinflammatory effect (JAMA, 256, 3110-3116, 1986) have also been studied as therapeutic agents for psoriasis. However, action mechanisms thereof have not yet been clear.
Although the above-mentioned factors and chemical substances have been known as remedies for skin and corneal diseases such as wounds and psoriasis, their effects have been yet far from satisfactory.
It is considered to supplementarily use an agent having the different action mechanism in order to enhance the effect of the conventional agent, heal promptly and to cure completely in the therapy of a skin or corneal disease. However, any satisfactory agent has not been yet provided.
Therefore, it is an object of this invention to provide a therapeutic agent for skin or corneal diseases, which has an action mechanism different from that of the conventional agent and is excellent in therapeutic effect.
In view of the foregoing circumstances, the present inventors have carried out an extensive investigation. As a result, it has been found that CPB-I, (calphobindin-I) which is an anticoagulant, is excellent in therapeutic action on skin and corneal diseases, and its action mechanism is different from that of the conventional agent, leading to completion of the present invention.